The stability of an organism's genome is governed by complex mechanisms that involve 1) the repair of[unreadable] DNA damage, 2) the regulation of progression through and transition between phases of the cell cycle and[unreadable] 3) the ability to reorganize chromatin structure. Each of these mechanisms is affected by the nature of the[unreadable] DNA damage and the signal transduction stimuli that alter transcriptional and post-translational activities.[unreadable] Defects in key components within these pathways can manifest in a variety of human disease, such as[unreadable] xeroderma pigmentosum with defects in NER repair and lesion bypass, ataxia telangiectasia, with defects in[unreadable] cell cycle control and intracellular signaling, Fanconi anemia with defective chromatin remodeling and[unreadable] replication restart and colon cancer with defects in mismatch or base excision repair. Thus, integrated[unreadable] responses to maintain of genomic stability are critical for long-term survival and organismal fitness.[unreadable] The focus of our investigations is on bis-electrophiles, a class of environmental and endogenous[unreadable] chemicals that upon exposure to DNA, form a complex mixture of lesions that can contribute to the initiation[unreadable] of cancer and premature aging. In the proposed studies, a series of hypotheses will be tested that will[unreadable] accomplish the following: 1) determine the mutagenic and cytotoxic consequences of replication of DNAs[unreadable] containing site-specific base lesions and the role that DNA repair plays in the modulation of the mutagenic[unreadable] potential of these lesions; 2) ascertain key genetic components of and the biochemical basis for a pathway[unreadable] to repair of interstrand crosslinks that occurs with high fidelity in the absence of homologous recombination;[unreadable] and 3) ascertain the extent to which the structure of specific DNA lesions that exist in a dynamic equilibrium[unreadable] between various species (monofunctional adduct, intra- and interstrand DNA crosslinks and DNA-protein[unreadable] crosslinks) affect nucleic acid transactions such as repair and replication.[unreadable] These investigations have direct application to human health since exposure to these compounds,[unreadable] whether from sources produced internally or as an environmental pollutant, contribute to cancer and[unreadable] premature aging. Investigations on the identity of the mutagenic and cytotoxic DNA lesions responsible for[unreadable] these diseases and their mechanisms of repair can ultimately lead to improved rational therapeutic designs.